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Agomelatine
Systematic (IUPAC) name
N-[2-(7-methoxynaphthalen-1-yl)ethyl]acetamide
Identifiers
CAS number 138112-76-2
ATC code N06AX22
PubChem 82148
ChemSpider 74141
Chemical data
Formula C 15H17NO2  
Mol. mass 243.301
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability <5% [1]
Metabolism hepatic (90%CYP1A2;10%CYP2C9)
Half life < 2 h [2]
Excretion  ?
Therapeutic considerations
Licence data

EU EMEA:link

Pregnancy cat.  ?
Legal status Prescription only
Routes Oral

Agomelatine (trade names Valdoxan, Melitor, Thymanax) is an antidepressant developed by the pharmaceutical company Servier. It is classified as a norepinephrine-dopamine disinhibitor (NDDI) due to its antagonism of the 5-HT2C receptor. Activation of 5-HT2C receptors by serotonin inhibits dopamine and norepinephrine release. Antagonism of 5-HT2C results in an enhancement of DA and NE release and activity of frontocortical dopaminergic and adrenergic pathways.[3][4] Agomelatine is also a potent agonist at melatonin receptors which makes it the first melatonergic antidepressant.[4][5] Because of its unique profile, agomelatine has not been associated with weight gain, sexual side effects, sleep problems or withdrawal syndrome; this is in contrast to most SSRIs and many antidepressants.[6][7]

Contents

Studies

Controlled studies with humans have shown that agomelatine is comparable to paroxetine (Seroxat, Paxil) and sertraline (Lustral, Zoloft), two SSRI antidepressants, in the treatment of major depression.[8] Agomelatine showed benefits over sertraline and paroxetine due to the lack of sexual side effects and discontinuation side effects. Because of its action upon the melatonin receptors, agomelatine also showed a marked improvement in sleep quality. There were no associated instances of daytime drowsiness.[7] Agomelatine has also demonstrated anxiolytic properties and thus may prove efficacious in the treatment of anxiety disorders.[9]

Development

Agomelatine was discovered and developed by the European pharmaceutical company Servier Laboratories Ltd. Servier continued to develop the drug and conduct phase III trials in the European Union. In March 2005 Servier submitted agomelatine to the European Medicines Agency (EMEA) under the trade names Valdoxan and Thymanax.[10] On 27 July 2006 the Committee for Medical Products for Human Use (CHMP) of the EMEA recommended a refusal of the marketing authorisation of Valdoxan/Thymanax (agomelatine). The major concern was that efficacy had not been sufficiently shown. The CHMP had no special concerns about the side effects.[10] In September 2007, Servier submitted a new marketing application for Valdoxan (agomelatine) to the EMEA.[11] On 20 November 2008, Valdoxan was given a positive opinion, with restrictions,[12] by the EMEA[11], and was subsequently given marketing authorisation in the European Union on 20 February 2009.[13] Release dates for agomelatine will depend on marketing arrangements in the individual countries of the EU.

In March 2006, Servier announced it had sold the rights to market agomelatine in the United States to Novartis.[14] Agomelatine is currently undergoing phase III clinical trials in the US.[15]

Novartis currently lists the drug as scheduled for submission to the FDA no earlier than 2012.

References

  1. ^ www.emea.europa.eu/
  2. ^ hit and run drug
  3. ^ Int J Neuropsychopharmacol. 2007 Oct;10(5):575-8. Epub 2007 Aug 6. PMID: 17681087
  4. ^ a b M. J. Millan, A. Gobert, F. Lejeune, A. Dekeyne, A. Newman-Tancredi, V. Pasteau, J.-M. Rivet & D. Cussac (September 2003). "The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways". The Journal of Pharmacology and Experimental Therapeutics 306 (3): 954–954. doi:10.1124/jpet.103.051797. PMID 12750432.  
  5. ^ Valdoxan: A Unique Mode of Action Valdoxan.com. Servier. Last accessed 6 July 2009.
  6. ^ Montgomery, Stuart (12 October 2006). "Major depressive disorders: clinical efficacy and tolerability of agomelatine, a new melatonergic agonist". European Neuropsychopharmacology. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6T26-4M3JHDF-4-1&_cdi=4910&_user=5141237&_orig=browse&_coverDate=09%2F30%2F2006&_sk=999839999.8994&view=c&wchp=dGLzVlz-zSkWz&md5=cdf177db589fd1ce1a96b53151ae2f64&ie=/sdarticle.pdf. Retrieved 6 July 2009.  
  7. ^ a b "Valdoxan: A New Approach to The Treatment of Depression". Medical News Today (MediLexicon International Ltd). 2005-04-05. http://www.medicalnewstoday.com/articles/22334.php. Retrieved 14 May 2009.  
  8. ^ Moser, Judith (2008-09-02). "Agomelatine Appears Superior to Sertraline for Treatment of Major Depressive Disorder: Presented at ECNP". DGDispatch (Doctor's Guide Publishing Limited). http://www.docguide.com/news/content.nsf/news/852571020057CCF6852574B8006445A8. Retrieved 2009-05-14.  
  9. ^ Millan, Mark; Brocco, M.; Gobert, A.; Dekeyne, A. (2004-07-30). "Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade". Psychopharmacology (Berlin, Heidelberg: Springer) 177 (4): 448–458. doi:10.1007/s00213-004-1962-z. ISSN 1432-2072. PMID 15289999. http://www.springerlink.com/content/11jgp8a5ttjap0j8/?p=da8d354b2db74b0ab18491fe585f60de&pi=3. Retrieved 2009-05-15.  
  10. ^ a b "Questions and Answers on Recommendation for Refusal of Marketing Authorisation". European Medicines Agency. 18 November 2006. http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-656-657-RQ&A-en.pdf. Retrieved 6 July 2009.  
  11. ^ a b "CHMP Assessment Report for Valdoxan". European Medicines Agency. 20 November 2008. http://www.emea.europa.eu/humandocs/PDFs/EPAR/valdoxan/H-915-en6.pdf. Retrieved 6 July 2009.  
  12. ^ Transaminases elavations and interactions with potent CYP 1A2 inhibitors (e.g. fluvoxamine, ciprofloxacin]
  13. ^ "VALDOXAN (AGOMELATINE), A NOVEL ANTIDEPRESSANT, RECEIVES EUROPEAN MARKETING AUTHORISATION". Servier UK. 25 February 2009. http://www.pharmiweb.com/PressReleases/pressrel.asp?ROW_ID=5770. Retrieved 6 July 2009.  
  14. ^ Bentham, Clara (2006-03-29). "Servier and Novartis sign licensing agreement for agomelatine, a novel treatment for depression". Servier UK. http://www.servier.co.uk/news/news-details.asp?StoryID=76. Retrieved 2009-05-15.  
  15. ^ "Clinical trials for agomelatine". ClinicalTrials.gov. National Institutes of Health. http://clinicaltrials.gov/ct2/results?term=agomelatine. Retrieved 6 July 2009.  

External links








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